Cytokines can affect T-cell proliferation and survival at many stages of the immune response. Dendritic cells (DCs) and plasmacytoid DCs (pDCs) secrete B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Agonist OX40-specific antibodies or an OX40-ligand–immunoglobulin fusion protein (not shown) can elicit enhanced CD4+ and CD8+ T-cell responses in tumour-bearing mice. First discovered in ‘90s this kinases, along with other member of the tyrosine kinase family resulted in the usage of the acronym JAK (Just Another Kinase). Janus kinases are believed to be present in unstimulated cells in an inactive form, ligand-induced receptor oligomerization serves as a trigger to signal the recruitment of JAKs to close proximity of the receptors. 2 – STATs (Signal Transducers and Activator of Transcription proteins) are latent transcription factors that until inactivated reside in the cytoplasm.
STAMs also known as signal-transducing adapter molecules (STAM1 and STAM2A) are adapter molecules with conserved VHS and SH3 domains that can be phosphorylated by JAK1-JAK3 and facilitate the transcriptional activation of specific target genes. StIP (stat-interacting protein), a WD40 protein, can associate with both JAKs and unphosphorylated STATs, perhaps serving as a scaffold to facilitate the phosphorylation of STATs by JAKs. SOCS proteins are a family of at least eight members containing an SH2 domain and a SOCS box at the C-terminus. 4 – Infact, in addition to the activation of STATs, JAKs can mediate the recruitment of other molecules involved in signal transduction such as the src-family kinases, protein tyrosine phosphatises, MAP kinases, PI3K kinase etc. Furthermore, the functions of activated STATs can be altered through association with other transcription factors and cofactors that are regulated by other signaling pathways. Humans are constantly exposed to fungi, but only a limited number of fungi cause severe infections. During initiation of the T-cell response, interleukin-15 (IL-15) might be involved in dendritic-cell (DC) activation. Both cytokines are also produced by epithelial cells, which in addition produce interleukin-6 (IL-6) and CXC-chemokine ligand 12 (CXCL12).
The centroblasts proliferate rapidly and differentiate into centrocytes, which compete for antigen fragments that are trapped at the surface of follicular dendritic cells (FDCs). The OX40-accentuated response is mainly attributed to enhanced CD4+ T-cell function (through increased cytokine production and increased survival of memory T cells), but CD8+ T cells are also essential for OX40-specific antibodies to have a positive impact in tumour-bearing mice. Subsequent sequencing studies revealed that the JAK family of protein tyrosine kinases differs markedly from other classes for the presence of an additional kinase domain.
A number of studies showed that the family of JAK kinases is involved in signaling by numerous interleukins as shown in the table below. The activation of the JAK family (for mammals: JAK1, JAK2, JAK 3 and Tyk2) occurs upon ligand-mediated receptor multimerization, when two JAKs are brought into close proximity and trans-phosphorylation is allowed.


The seven mammalian STATs bear a conserved tyrosine residue near the C-terminus that is phosphorylated by JAKs. The best characterized of these is SHP-1, it contains two SH2 domains and can bind to either phosphorylated JAKs or phosphorylated receptors to facilitate dephosphorylation of these activated signaling molecules. In addition, a small kinase inhibitory region located N-terminal to the SH2 domain has been identified for SOCS1 and SOCS3. These molecules process downstream signals via the Ras-Raf-MAP kinase and PI3 kinase pathway which results in the activation of additional transcription factors.
Thus the integration of input from many signaling pathways must be considered if we are to understand the biological consequences of cytokine stimulation. After T-cell receptor (TCR) ligation of peptide–MHC, substantial T-cell clonal expansion occurs and might be driven, in part, by IL-2.
Epithelial cells also produce thymic stromal lymphopoietin (TSLP) to enhance the expression of APRIL by DCs. B-cell mutants that have high-affinity B-cell receptors internalize antigen and present peptide fragments to TF cells, which then provide selective CD40 ligand (CD40L)-dependent rescue signals for B cells.
It has been shown both in human tumours and mouse tumour models that OX40+ T cells are found in a wide variety of solid malignancies; therefore, the OX40-specific enhancement probably occurs in or near the tumour microenvironment.
To denote this unique structural feature, these kinases were renamed as “Janus kinases” (JAK) in reference to an ancient two-faced Roman God of gates and doorways. In summary it appears that specific JAK kinases, either alone or in combination with other JAKs, may be preferentially activated depending on the type of the receptor that is being activated and subsequentially different STATs are going to be activated. Once activated JAKs can phosphorylate additional targets, including both the receptors and their major substrates, the STATs. This phosphotyrosine permits the dimerization of STATs through interaction with a conserved SH2 domain. The pathogenesis of fungal infections involves several virulence factors that allow fungal survival and persistence in the host, eventually leading to tissue damage. Phosphorylated and dimerized STATs enter the nucleus where can bind specific regulatory sequences to activate or repress transcription of target genes. The SOCS can affect their negative regulation by three means: by binding phosphotyrosines on the receptors (SOCS physically block the recruitment of signal transducers to the receptor), by bindind directly to JAKs or to the receptors to specifically inhibit JAK kinase activity, by the interaction with the elongin BC complex and cullin 2 (so facilitating the ubiquitination of JAKs and receptors, targeting them for proteasomal degradation). The resulting cytokine milieu might create a survival niche for plasma cells in the intestinal lamina propria.
Centrocytes that are positively selected leave the germinal centre (GC) and differentiate into memory B cells or mature into long-lived plasma cells. Most tumour models that have been 'cured' through OX40 ligation are MHC class II negative; therefore, indirect priming of tumour-antigen-specific T cells by professional antigen-presenting cells (APCs) is probably required to initially stimulate CD4+ T cells at the tumour site.


Also, some species of Candida can grow in different forms, such as yeasts, blastospores, pseudohyphae and hyphae, depending on infection sites.
The massive cell death that occurs during the contraction phase results in the loss of most antigen-specific T cells. After mice have been cured by OX40 ligation, they are immune to subsequent rechallenge with the primary tumour, but they are not immune to tumours of a different origin (indicating enhanced tumour-specific T-cell-mediated memory). Although there is evidence that STATs can be modified by sumoylation, the function of that modification in negative regulation is not yet known. Cryptococcus neoformans yeasts become coated with a capsule, and the filamentous fungi (for example, Aspergillus spp., Fusarium spp. Both IL-15 and IL-7 might rescue T cells from cell death at this stage, thereby allowing memory T-cell generation. The structures of the A1 and C2 modules, but not the X2 module, have been solved by crystallographic studies.
The T cells then upregulate expression of CXC-chemokine receptor 5 (CXCR5) and migrate into B-cell follicles (white arrow). Memory T cells are maintained long term by undergoing a low level of proliferation, which depends on IL-15.
The cysteine pattern of the X2 module in BAFF-R does not conform entirely to that of canonical conventional modules. Although such morphogenesis is an example of a developmental change, it is distinct from the life cycles that are displayed by other organisms, as there is no evidence that cycling between different morphotypes is obligatory for fungi. Instead, morphological transition, often connected with metabolic flexibility, is a mechanism that some fungi have evolved to adapt to different environments.Associations between morphogenesis and virulence have long been presumed for dimorphic fungi that are human pathogens, as one morphotype exists in the environment or during commensalism, and others in the host during the disease process125. However, although morphological flexibility could be a key contributor to fungal invasion, no molecular data unambiguously establish a role for fungal morphogenesis as a virulence factor126. In addition, as virulence genes are co-regulated with cell morphogenesis, the ability to switch from yeast to hyphal growth in response to various environmental signals is considered to be inherent to Candida virulence. Both yeast and hyphal forms of fungi clearly have a wide range of attributes that contribute actively to fungal infectivity.
Undoubtedly, fungal morphogenesis, through antigenic variability, phenotypic switching and dimorphic transition, implicates the existence of many recognition and effector mechanisms to oppose fungal infectivity at the different body sites.



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